DESCRIPTION (from applicant's abstract): The long-term goal of this study is to understand the function and dysfunction of hearing at the molecular level. Hearing impairment is the most common human sensory disorder. Approximately 70 million people worldwide suffer from hearing loss over 55 dB. Genetic factors are one of the most important causes for hearing impairment. Approximately one in every 2,000 children is born with severe to profound hearing loss due to a genetic cause. Non-syndromic hearing loss occurs in isolation, and it accounts for approximately 80% of hereditary deafness. Studies on the molecular basis of non-syndromic hearing loss, especially the late onset forms, are not only important for improving our understanding of the molecular mechanisms of auditory development and function, but also for developing more precise genetic counseling and therapeutics for both genetic and environment-related hearing impairment. We have mapped two new deafness loci, DFNA29 and DFNA32, using linkage analysis on two large US families with non-syndromic autosomal dominant progressive hearing loss. The PI proposes to identify the responsible genes, and to explore their function in the hearing process. The following specific aims are proposed: (1) Refine the critical region of DFNA29 and DFNA32 using recombinational mapping and linkage disequilibrium strategies. (2) Establish permanent cell lines from both affected and unaffected individuals by Epstein-Barr virus transformation. (3) Identify the molecular basis of these loci using a positional candidate gene approach. (4) Establish expression patterns of the genes responsible for DFNA29 and DFNA32 in the developing auditory and vestibular systems using PCR, RT-PCR, and RNA in situ hybridization. This specific aim represents a long-term direction of the study.